Coronary Microvascular Dysfunction in Asymptomatic Patients Affected by Systemic Sclerosis　– Limited vs. Diffuse Form –

Abstract

Background: This observational study was designed to evaluate the prevalence of coronary microvascular dysfunction (CMD) in asymptomatic patients affected by systemic sclerosis (SSc), stratifying the results according to the limited (lcSSc) and the diffuse (dcSSc) forms of the disease.

Methods and Results: We enrolled 19 consecutive asymptomatic patients with dcSSc (n=7) or lcSSc (n=12). In all subjects, coronary flow reserve (CFR) was assessed by measuring diastolic coronary flow velocities in the left anterior descending artery by pulsed wave Doppler at baseline and after dipyridamole infusion (0.84 mg·kg⁻¹·6 min⁻¹). Wall motion score index was evaluated at baseline and during stress. We enrolled 20 healthy subjects as controls. Mean CFR was 1.96±0.62 in patients and 2.69±0.47 in controls (P<0.001). Abnormal values of CFR (≤2) were significantly more prevalent in patients than in controls (10/19 vs. 0/20; P<0.001) and in the dcSSc subgroup than in the lcSSc subgroup (6/7 vs. 4/12; P=0.05). An inverse relationship between disease duration (from time of onset of Raynaud’s phenomenon) and CFR value was observed in the lcSSc group (correlation coefficient −0.583; P=0.046). Neither patients nor controls had wall motion abnormalities during dipyridamole administration.

Conclusions: A blunted CFR, most likely because of CMD, is more frequent in patients affected by the dcSSc form in the early stages of the disease, whereas it seems to appear later in lcSSc. (Circ J 2015; 79: 825–829)

Systemic sclerosis (SSc) is a connective tissue disease that is characterized by vascular dysfunction and excessive fibrosis. Most commonly, SSc presents with Raynaud’s phenomenon, followed by progressive induration and stiffening of the skin because of the accumulation of collagen with variable involvement of the joints, esophagus, small bowel, large bowel, heart, lungs and kidneys.¹ Because of the different patterns of skin involvement, SSc can be divided into 2 subgroups, the diffuse (dcSSc) and limited (lcSSc) forms, the clinical course differing from one another with a more precocious and severe organ involvement in dcSSc than in lcSSc.²

The estimated clinical prevalence of cardiac manifestations in patients with SSc is 15–35%, even if in the majority of cases it remains subclinical.³ When clinically overt, cardiac involvement is a recognized marker of poor prognosis.⁴ Although a popular model to explain the pathogenesis of vascular disease in SSc is not yet fully proven, it is suggested that an endothelial injury occurs early in the disease process leading to endothelial cell dysfunction. Myofibroblasts, drawn into the vessel wall by cellular growth factors, contribute to the thickening of the intimal layer, compromising regional blood flow by narrowing the vascular lumen. Endothelium dysfunction also results in an imbalance of vasoactive factors, including overproduction of the vasoconstrictor, endothelin-1, and underproduction of the vasodilators, nitric oxide (NO) and prostacyclin.⁵

Reduced coronary flow reserve (CFR) can be demonstrated late in the course of the disease in patients with SSc. A severe blunting of CFR, measured invasively during cardiac catheterization, has been demonstrated in patients with diffuse cutaneous SSc with established myocardial involvement and normal coronary angiograms. Thus, in the absence of coronary stenosis, the abnormal CFR is believed to result from structural remodeling of the small coronary arteries and arterioles.⁶

The aims of our study were first, to assess the prevalence of abnormal CFR during dipyridamole stress echocardiography in consecutive asymptomatic patients affected by SSc compared with healthy controls and second, to compare the CFR results of patients affected by lcSSc and those affected by dcSSc.

Methods

Study Population

Consecutive patients affected by SSc who fulfilled the American College of Rheumatology criteria for SSc⁷ and/or the revised criteria published in 2001 for an earlier diagnosis,⁸ who were between 18 and 75 years of age and had no clinical history or signs of coronary artery disease, arrhythmia or other cardiac diseases, were included in our study. A group of healthy volunteers served as normal controls. According to literature data,⁹ we used ‘two proportions power analysis’ to establish the study size, which resulted in 20 patients vs. 20 controls.

Exclusion criteria were: (1) technically poor acoustic window precluding the visualization of the left anterior descending coronary artery (LAD), (2) impossible peripheral vein cannulation, (3) symptoms suggesting heart involvement, (4) severe pulmonary functional impairment leading to oxygen therapy use, (5) contraindication to dipyridamole infusion such as asthma or severe chronic obstructive pulmonary disease, significant internal carotid artery stenosis and severe atrioventricular block, (6) inability or refusal to give informed consent. All the study subjects were requested to avoid xanthine-containing food and drinks for more than 24 h before evaluation.

All patients and controls underwent a complete recording of medical history, physical examination and ECG evaluation. In addition, conventional and stress transthoracic echocardiography with CFR measurement was performed.

Stress Echocardiography

Transthoracic stress echocardiographic studies were performed with commercially available ultrasound machines (iE 33, Philips Ultrasound, Andover, MA, USA) equipped with a multifrequency phased-array sector scan probes (S3–S8) and with second harmonic technology. Two-dimensional echocardiography and 12-lead ECG monitoring were performed during dipyridamole infusion (up to 0.84 mg over 6 min).¹⁰ Echocardiographic images were semiquantitatively assessed using a 17-segment, 4-point scale model of the left ventricle.¹¹ A wall motion score index was calculated by dividing the sum of individual segment scores by the number of interpretable segments. Ischemia was defined as stress-induced new and/or worsening of preexisting wall motion abnormality. A test was considered positive for ischemia only on the basis of wall motion analysis. Rest wall motion abnormality was considered to be akinetic or dyskinetic myocardium with no thickening during stress. The left ventricular ejection fraction was assessed in the standard 4-chamber view. CFR was assessed during the standard stress echo examination by intermittent imaging of both wall motion and flow velocity in the LAD. The flow velocity signal in the mid-distal portion of the LAD was searched for in the low parasternal long-axis section under the guidance of color Doppler flow mapping.¹⁰ All studies were digitally stored to simplify off-line reviewing and measurements. Coronary flow parameters were analyzed off-line using the built-in calculation package of the ultrasound unit. Flow velocities were measured at least twice for each study, namely at baseline and at peak stress (before aminophylline injection). At each time point, 3 optimal profiles of peak diastolic Doppler flow velocities were measured, and the results were averaged. CFR was defined as the ratio between hyperemic peak and basal peak diastolic coronary flow velocities. A CFR value ≤2.0 was considered abnormal.¹²

The study protocol was approved by the local ethics committee and written, informed consent was given by all the subjects before the study, according to the Declaration of Helsinki.

Statistical Analysis

Data are expressed as a mean±SD or percentage. Data were analyzed using independent t-test or Chi-square or Fischer exact test as appropriate. A P-value <0.05 was considered statistically significant. Data management and analysis were performed using IBM SPSS Statistics 19.

Results

We enrolled 19 patients (7 with dcSSc, 12 with lcSSc), and 20 healthy volunteers. None of them had history of atherosclerotic coronary disease or symptoms that suggested cardiac involvement.

The baseline characteristics of the study population are reported in Table 1, and the subgroup analysis with comparison between dcSSc and lcSSc patients is shown in Table 2.

Table 1. Clinical Findings in Asymptomatic Patients Affected by Systemic Sclerosis and Controls

	Patients (n=19)	Controls (n=20)	P value
Age (years)	51.9±13.6	37.1±10.8	0.001
Female	16 (84.2%)	5 (25%)	<0.001
Smoker	10 (52.6%)	7 (35%)	0.27
Dyslipidemia	3 (15.8%)	1 (5%)	0.342
Diabetes mellitus	0	0	1
Arterial hypertension	5 (26.3%)	3 (15%)	0.45
Basal peak diastolic velocity (cm/s)	47.86±15.35	23.42±7.21	<0.001
Hyperemic peak diastolic velocity (cm/s)	94.21±39.88	62.54±20.15	0.005
CFR	1.96±0.48	2.69±0.47	<0.001
CFR ≤2	10 (52.6%)	0	<0.001

CFR, coronary flow reserve.

Table 2. Clinical Findings in Asymptomatic Patients With Diffuse vs. Limited Systemic Sclerosis

	dcSSc (n=7)	lcSSc (n=12)	P value
Age (years)	46.86±14.31	54.83±12.82	0.25
Female	5 (71.4%)	11 (91.7%)	0.52
Smoker	4 (57.1%)	6 (50%)	1
Dyslipidemia	0	3 (25%)	0.26
Diabetes mellitus	0	0	1
Arterial hypertension	0	5 (41.7%)	0.11
Disease duration years	5.43±3.15	15.83±12.99	0.02
Digital ulcers	3 (42.9%)	3 (25%)	0.62
GI involvement	4 (57.1%)	10 (83.3%)	0.31
ANA-n	4 (57.1%)	2 (16.7%)	0.13
ANA-c	0	10 (83.3%)	0.001
Scl-70	6 (85.7%)	1 (8.3%)	0.002
Calcium antagonists	5 (71.4%)	6 (50%)	0.63
Prostacyclin analogue	2 (28.6%)	4 (33.3%)	1
Endothelin receptor antagonist	1 (14.3%)	1 (8.3%)	1
Nitric oxide donor	0	1 (8.3%)	1
ACEI or ARB	0	5 (41.7%)	0.11
Acetylsalicylic acid	6 (85.7%)	5 (41.7%)	0.15
Basal peak diastolic velocity (cm/s)	45.93±18.04	48.98±14.30	0.71
Hyperemic peak diastolic velocity (cm/s)	78.87±36.83	103.16±40.32	0.20
CFR	1.72±0.32	2.10±0.51	0.06
CFR ≤2	6 (85.7%)	4 (33.3%)	0.05

ACEI, angiotensin converting enzyme inhibitor; ANA, antinuclear antibodies; ARB, angiotensin receptor-blocker; CFR, coronary flow reserve; dcSSc, diffuse systemic sclerosis; GI, gastrointestinal; lcSSc, limited systemic sclerosis; Scl-70, anti-topoisomerase antibodies.

Doppler measurement demonstrated a higher prevalence of reduced CFR in patients than in controls (Table 1), and in dcSSc than in lcSSc patients (Table 2, Figure 1). No association between autoantibodies [ANA-n (P=0.63), ANA-c (P=0.37) and Scl-70 (P=0.35)] and reduced CFR was found.

Figure 1.

Assessment of coronary flow reserve (CFR). Subject with normal CFR, basal peak diastolic velocity (A) and hyperemic peak diastolic velocity (B). Patient with the limited form of systemic sclerosis with pathologic CFR, basal peak diastolic velocity (C) and hyperemic peak diastolic velocity (D).

Finally, there was an inverse relationship between the time since onset of Raynaud’s phenomenon and the CFR value in the lcSSc subgroup (correlation coefficient −0.583; P=0.046) (Figure 2).

Figure 2.

Correlation between coronary flow reserve (CFR) values and disease duration in patients with the limited form of systemic sclerosis (lcSSc).

Neither patients nor controls had wall motion abnormalities under baseline conditions or during dipyridamole stress.

Discussion

It is well known that CMD can be assessed by both invasive and noninvasive methods.^10,13,14 The results of the present study demonstrate that asymptomatic SSc patients, evaluated in a noninvasive manner, had a higher prevalence of reduced CFR compared with healthy controls. Moreover, we found that the dcSSc subgroup had a higher prevalence of impaired CFR than the lcSSc subgroup and that lcSSc patients developed a significant reduction in CFR later in the course of the disease.

The presence of CMD has been already demonstrated in various chronic diseases in which cardiac abnormalities are frequent, such as systemic lupus erythematosus and rheumatoid arthritis.¹⁵ These previous studies prompted us to investigate the prevalence of CMD in SSc.

The prevalence of heart involvement in SSc is often clinically underestimated. In an international meta-analysis published in 2005, the clinical prevalence was reported to be approximately 10%,¹⁶ whereas postmortem studies reported an incidence of heart involvement in more than half of the patients.¹⁷ When clinically overt, myocardial involvement confers a poor prognosis on SSc patients, with a mortality rate of 70% at 5 years.³ For this reason, the identification of preclinical heart involvement has pivotal importance.

Recent studies have demonstrated the presence of a silent coronary microvascular involvement in SSc patients that were examined by noninvasive tests such as adenosine or dobutamine stress echocardiography.^9,18–20

Our study is the first to demonstrate a statistically significant correlation between the duration of disease and the CFR value in lcSSc patients. We believe that these data are important because they highlight the benefit of periodic cardiac evaluation of CFR in this subgroup, particularly in view of the negative prognostic significance of a reduced CFR, as shown by Vacca et al.¹⁸

We confirm the findings of Vacca et al relative to the greater prevalence of reduced CFR in dcSSc than in lcSSc. Compared with the latter study, however, we used a more conservative cutoff value of CFR (ie, ≤2.0 instead of ≤2.5 previously used by Vacca et al). This lower cutoff for CFR is the currently accepted standardized value reported in the consensus statement of the European Association of Echocardiography.¹⁰ Moreover, in our study we used dipyridamole stress echocardiographic examination, a single, noninvasive and relatively inexpensive test, which allowed us to simultaneously analyze CFR and the wall motion score index. This is an important difference to the recent study by Vacca et al in which they used a 2-step test: adenosine transthoracic echocardiography sometimes with contrast medium administration to measure CFR, and dobutamine stress echocardiography to assess the wall motion score index. None of the patients with low CFR underwent invasive or computed tomography coronary angiography because none of the patients had associated symptoms or wall motion abnormalities. We interpreted the absence of symptoms and of kinetic abnormalities as a sign of the absence of significant epicardial coronary stenosis. The absence of wall motion abnormalities during dipyridamole stress despite reduced CFR can be explained by the fact that, under these circumstances, cardiac workload is only slightly increased and oxygen supply is still enough to match demand.

The link between microvascular dysfunction and unfavorable long-term prognosis has been established in many studies²¹ and the negative prognostic significance of an early silent coronary microvascular involvement in SSc patients has been already decribed.¹⁸ Our results, however, highlight the importance of early evaluation of CFR in these patients for prognostic stratification. In fact, the dcSSc patients in our study had a shorter disease duration than in those with lcSSc (5.43±3.16 years vs. 15.83±12.99 years, P=0.02). The higher prevalence of reduced CFR, despite the shorter disease duration, could be the consequence of a more aggressive microvascular involvement, reflecting the different systemic course of the disease in the 2 subgroups.² In our study, the different timing of coronary microvascular involvement is also confirmed by the inverse relationship between CFR values and disease duration in lcSSc, but not in dcSSc. It seems, in fact, that in dcSSc the coronary microvascular involvement starts aggressively at the beginning of the disease whereas in lcSSc the microvessels are affected in a more indolent manner, leading to CFR reduction later in the course of the disease. In view of all this, we suggest that a noninvasive, short and inexpensive examination, such as dipyridamole stress echocardiography, is a cost-effective tool to risk-stratify patients with SSc.

Study Limitations

First of all, patients and controls were not age matched. However, Uren et al demonstrated that there is no difference in CFR measured by positron emission tomography in healthy subjects aged between 20 and 60 years.²² Second, we did not perform coronary angiography in patients with reduced CFR. However, none of the patients had wall motion abnormalities or cardiac symptoms during dipyridamole stress, which in our opinion excluded the presence of epicardial stenosis and did not justify angiography. Third, the study was designed to evaluate differences in CFR between asymptomatic patients affected by SSc and controls; we found a difference between the prevalence of reduced CFR in dcSSc and in lcSSc patients in a subgroup analysis. However, even if the statistical significance is borderline (P=0.05), the percent difference is considerable (85.7% vs. 33.3%) and is also supported by the trend towards a higher mean CFR value in lcSSc patients. Finally, all the patients came from a single clinical centre with an obvious selection bias.

Conclusions

CMD was found in almost half of the asymptomatic SSc patients enrolled. It was especially evident in patients affected by the diffuse form of the disease, whereas the limited form seemed to have a delayed involvement. These findings highlight the importance of an exhaustive cardiac evaluation in all SSc patients, even at an early stage, including noninvasive estimation of CFR.

Disclosures

The authors declare no conflicts of interest. The study did not have any funding support.

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